Long Telomeres may also be Problematic

Researchers here provide initial evidence to suggest that very long telomeres may be problematic in human cells - that manipulating our biochemistry to push telomere length outside evolved norms in either direction will cause issues. Telomeres are repeated DNA sequences that cap the ends of chromosomes. There is considerable interest in telomere length in connection with aging, as average telomere length diminishes with age, though this is a statistical effect across populations and not very useful for individual predictions. There is a lot of variation over time and by health status in any given individual and between any two individuals of the same age and fitness. On the whole telomere length looks a lot like a marker of aging rather than the cause of problems: the groups that primarily seek to engineer longer telomeres in search of a way to slow aging are probably putting the cart before the horse.

Tissues are made up of somatic cells that are restricted in the number of divisions they can undertake, and supported by a small number of stem cells that are not restricted in that way. Each cell division results in a loss of telomere length, and once telomeres are too short the cell becomes senescent or self-destructs. New cells with long telomeres are created by stem cells, and those stem cells maintain long telomeres themselves via the use of telomerase. Thus average telomere length in somatic cells would seem to be a measure of some combination of stem cell activity and cell division rates - and it is known that stem cell populations decline with age. Researchers have demonstrated slowed aging in mice through increased telomerase activity, but it is far from clear as to identity of the important mechanisms in this effect: greater stem cell activity seems the most plausible, but there are a range of other options.

Ever since researchers connected the shortening of telomeres - the protective structures on the ends of chromosomes - to aging and disease, the race has been on to understand the factors that govern telomere length. Now, scientists have found that a balance of elongation and trimming in stem cells results in telomeres that are, as Goldilocks would say, not too short and not too long, but just right. "This work shows that the optimal length for telomeres is a carefully regulated range between two extremes. It was known that very short telomeres cause harm to a cell. But what was totally unexpected was our finding that damage also occurs when telomeres are very long."

Telomeres are repetitive stretches of DNA at the ends of each chromosome whose length can be increased by an enzyme called telomerase. Our cellular machinery results in a little bit of the telomere becoming lopped off each time cells replicate their DNA and divide. As telomeres shorten over time, the chromosomes themselves become vulnerable to damage. Eventually the cells die. The exception is stem cells, which use telomerase to rebuild their telomeres, allowing them to retain their ability to divide, and to develop ("differentiate") into virtually any cell type for the specific tissue or organ, be it skin, heart, liver or muscle - a quality known as pluripotency. These qualities make stem cells promising tools for regenerative therapies to combat age-related cellular damage and disease. "In our experiments, limiting telomere length compromised pluripotency, and even resulted in stem cell death. So then we wanted to know if increasing telomere length increased pluripotent capacity. Surprisingly, we found that over-elongated telomeres are more fragile and accumulate DNA damage."

The reasearchers began by investigating telomere maintenance in laboratory-cultured lines of human embryonic stem cells (ESCs). Using molecular techniques, they varied telomerase activity. Perhaps not surprisingly, cells with too little telomerase had very short telomeres and eventually the cells died. Conversely, cells with augmented levels of telomerase had very long telomeres. But instead of these cells thriving, their telomeres developed instabilities. "We were surprised to find that forcing cells to generate really long telomeres caused telomeric fragility, which can lead to initiation of cancer. These experiments question the generally accepted notion that artificially increasing telomeres could lengthen life or improve the health of an organism."

The team observed that very long telomeres activated trimming mechanisms controlled by a pair of proteins called XRCC3 and Nbs1. The lab's experiments show that reduced expression of these proteins in ESCs prevented telomere trimming, confirming that XRCC3 and Nbs1 are indeed responsible for that task. Next, the team looked at induced pluripotent stem cells (iPSCs), which are differentiated cells (e.g., skin cells) that are reprogrammed back to a stem cell-like state. iPSCs - because they can be genetically matched to donors and are easily obtainable - are common and crucial tools for potential stem cell therapies. The researchers discovered that iPSCs contain markers of telomere trimming, making their presence a useful gauge of how successfully a cell has been reprogrammed. "Stem cell reprogramming is a major scientific breakthrough, but the methods are still being perfected. Understanding how telomere length is regulated is an important step toward realizing the promise of stem cell therapies and regenerative medicine."

Link: http://www.salk.edu/news-release/goldilocks-effect-aging-research/

Comments

Hi, this is most interesting.

I wager from Mrs.Parrish Bioviva results that it's a very intricate and delicate balance.
She increased her telomere size and was (supposedly) rejuvenated at least 10 or 15-20 years. From gaining about a full 1 KB (1000 basepairs nucleotides TTAGGG repeats) of telomeric DNA.
So far there has no been much follow-up research on her cancer and tumor markers - has a (more) cancer formed since she did the therapy on herself or it has stayed the same ?

Some studies say : ''Animals studies point to no and even reduced risk of cancer.'' by increasing telomere size - I believe it's a middle ground where too much of a good thing can be just as a bad as not enough - this is why telomerase can actually become a 'promoter' of cancer formation (like in this study through chromosome instability - perhaps telomerase makes errors and uncaps also rather that just cap, it does so with Shelterin Telomere Complex proteins - but it's an 'open door' to create chromosomal errors (As in this study - when telomerase is excessive and constant). I try to transpose that with Hydras who are immortal and have telomerase in permanence - and Wonder why their ultra-elongated chromosomes don't become unstable from excessive telomerase in ther germ cells. I believe it's due to them 'aging' and 'reverting' - the loop - allows telomerase to be 'sporadically' coming back on and on - but never in a Constant presence on the télomères, It does 'telomere elongation' in 'Bursts' and gets away - to protect the integrity of telomeres and chromosomes/errors (just like the 'hit and run fashion', by exposing itself less to the telomere it mitigates chances of cancer formation by mutational error/chromosomal fusion/breaking/uncapping during elongation). So, in a sense, if transposed to Mrs.Parrish, a stronger immune system with better longer telomeres in leukocytes, macrophages, T-Cell, NK-cell, etc will Detect and Kill better the cancer from forming (even if their occurrence increases), an improve immune system is stronger in face of a higher load of mutation (by excess telomerase). Here, I think the chromosomal dysfunction end being way too much and compromise the genome - long telomeres or not. Telomere stability is - thus, far more important than length (as seen in very short telomeres who can be soldly capped and continued on 'as stable enough', cancers highjack that mechanism of ultra-telomerase (not all though some are telomerase-deficient and ALT fusion/aberration cheating - again showing that chromosomal disruption is fatal - short or tall telomeres). In her case, she had elongated telomeres and its a good thing.

With this knowledge here of increased cancer incidence by chromosome fragmentation from excess telomerase hanging at telomeres - means it's 'dose' thing. A Bioviva telomerase lengthening therapy should very sporadic - like once a year or even once 5 years to reset back telomere length. And, thus, avoiding high cancer formation from constant telomerase presence.

It could also be done with anti-cancer herbs, elements in combination to Knock any chance of spontaneous cancer formation during telomerase presence (think of Astragalus/TA-65 - who has the power to increase telomerase/telomere size of good cells - and kill cancers - at the same time (by targetting the redox properties of cancer cells, only).

In doing so, you incraese immune power - destroying the formed cancers in the next year to 5 years - and revert back to original telomere length years ago. Thus, Bioviva telomerase therapy is still valuable - despite this study here - we have to wait for her organ/tissue cancer results to know what's going for that point. If cancer appeared, we may heading into trouble and thus this study is very true; but we shouldn't give up on. The test should be done again - but with anti-cancer elements mixed-in - and see, if it could be a very occasionnal thing each 5 or 10 years.

PS: some studies showed that telomere size and epigenetic DNA methylation can be uncoupled. But, some others showed that indeed, global demethylation is happening at the same time as telomere loss (aging). And since, high telomeres are hypermethylated; it would mean increasing telomere size reverse epigenetic aging changes (since the methyl count, as 5-methylcytosine for example, is in direct correlation between telomere length and epigenetic methylation levels). Demethylated telomeres are mostly, short, unstable and uncapped. Here, in this study, it's tall telomeres. And the reason is, constant presence of telomerase = ultra-huge telomeres (way above the original 'youngest' highest telomeres), that is incompatible - it creates chromosomal aberrations/unstability as seen in a study recently that showed ultra-long telomeres from constant telomerase created genomic chromosome dysfunction - creating cancer then.

Posted by: CANanonymity at December 6th, 2016 6:07 PM

PPS: As for SENS therapy of Completely Eliminating Telomerase - to kill most cancers. A good thing - too. But, there is a but, we lose telomeres, telomerase helps on that point. Most long-lived post-mitotic somatic cells are entirely devoid of telomerase; yet it was showed in mice such TGTERT mice that lifespan was increased by telomerase - and did not get more cancer (although these are mice not humans... there may a 'big effect' in mice but in humans the translatability would be weak - only improving health - but increasing the chance of cancer with longer telomeres, even if we have a stronger immune system. It's a very balancing act).
I suggest doing the SENS therapy and then getting back to BioViva Therapy, alternating, alone or in combination each interval of time (like 5 years, switching Bio to Sens, Sens to Bio...), is going to be the best - to reap the good of telomerase while avoiding the bad. We will discover a lot of things for sure (you know like when you read, 'some people' developped such symptoms or such symptoms during the trials...it'S going to happen.. it will need to be fine tuned). Perhaps, we won't even need Bioviva and SENS all therapies alone will do (but it's better, sometimes, to combine and alternate just to make sure the SENS is still relevant in potency effect). Fun times.

Posted by: CANanonymity at December 6th, 2016 7:35 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.